In-line IV drug delivery pack with controllable dilution

ABSTRACT

An in-line drug delivery pack that connects in-line with an intravenous (IV) line and allows for the mixing of diluent with a drug reagent to be delivered to the patient. An internal drug bed bypass mechanism is tailored to apportion diluent flow between the bypass and the drug bed. The apportionment is selected to achieve a solution concentration suitable for IV administration as the dried reagent is dissolved. Thus, both dissolution and precisely tailored dilution are performed in the same simple device.

REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/214,558, now U.S. Pat. No.______ , which is a continuationof U.S. patent application Ser. No. 09/717,796, now U.S. Pat. No.6,428,505, which claims the benefit of priority to U.S. provisionalapplication No. 60/166,597, filed Nov. 19, 1999, all of which are herebyincorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates generally to drug delivery devices,and more particularly to devices for storing, transporting anddissolving dry reagents.

[0004] 2. Description of the Related Art

[0005] Medical treatments often involve solutions or suspensions ofdrugs or other reagents to be injected into the human body. Mixing andinjecting such solutions can be extremely expensive and inaccurate.Thus, there are a number of problems with current methods of intravenousdrug delivery.

[0006] Conventional methods involve administration of drug solutionsderived from thawed preparations of previously frozen drug solutions orfrom drug solutions produced by connection of a diluent pouch with adrug-containing vial. The later delivery method requires considerablemanipulation to place the dry drug formulation into solution prior toadministration to the patient. Among the greatest problems associatedwith existing methods are the direct and indirect costs of the deliverysystems. For frozen solutions indirect costs are associated withfreezers, temperature monitoring equipment and procedures required tomaintain drug supplies. Direct costs are associated with the laborrequired to thaw the frozen solutions prior to administration to thepatient. Similarly, for preparation of drug solutions using dry drug andseparate diluent preparations, costs are associated with the requirementfor multiple components and the manipulation required to place the drugin solution.

[0007] The requirement for freezing drug solutions or use of multiplecomponents to prepare drug solutions results from the instability ofmany drugs once the drugs are activated or placed into solution. Overtime, sometimes within a matter of 1 to 2 hours, the efficacy of drugsdiminishes after they are placed in solution. Accordingly, additionalcosts are associated with the waste associated with formation of drugsolutions that are not administered to the patient in a timely manner,for example, when changes in prescription or patient movement precludeadministration of the prepared drug solution.

[0008] The manipulation associated with combining a separate drug vialand a diluent from a pouch includes threading of a separatedrug-containing vial into a threaded receptacle. Inadequate threadingtogether of these components results in leakage of the diluent or drugsolution from this junction and breaches the sterile barrier intended tobe formed between the drug vial and the diluent pouch. The repeatedeffort required to thread these separate components together has lead tocarpal tunnel syndrome among healthcare providers. For certain deliverysystems, an internal cork must be removed by manipulation through thewalls for the diluent pouch in order to expose the dry drug within thevial to the diluent. Omission of this step results in administration ofdiluent without drug to the patient.

[0009] Moreover, in order to properly dissolve the drug in the diluentthe combination of components must be vigorously agitated. It is oftennot possible to be absolutely certain that all the drug has been removedfrom the vial. Because of the translucent nature of the diluent pouch,it is also sometimes difficult to differentiate between dissolved drugand minute, undissolved drug particles within the diluent pouch. Ifundissolved drug particles are administered to patients they present aserious potential hazard to the patient of an embolus capable ofoccluding small blood vessels.

[0010] Administration of the additional fluids required foradministration of drug solutions using a secondary set of fluids, beyondthose administered to maintain electrolyte balance, results in fluidproblems in patients with fluid retention maladies.

[0011] The volume occupied by existing delivery systems and/or therequirement for maintaining a frozen environment prevents these systemsfrom being used in automated dispensing devices.

[0012] An alternative to use of these delivery systems is thepreparation of drug solutions by pharmaceutical personnel from bulkcontainers of drug. These procedures require a considerable amount ofeffort by these personnel and represents a serious hazard to thepharmacy and drug administration personnel due to the toxicity of someagents.

[0013] U.S. Pat. No. 5,259,954 to Taylor, issued Nov. 9, 1993(hereinafter “the '954 patent”) and U.S. Pat. No. 5,725,777 issued Mar.10, 1998 (hereinafter “the '777 patent”) disclose a drug pack or“reagent module” suitable for storing dry reagents and for preparingsolutions for administration by passing fluid through the pack. Thesereferences are incorporated herein by reference. The '777 patentdiscloses two embodiments in which a porous compression elementconstantly exerts an inward force on a dry reagent bed, keeping itcompacted even as the bed is eroded by passing fluid through the porouscompression element and through the bed. This arrangement advantageouslyenables efficient uniform dissolution of the reagent bed by avoidingchannel formation through the reagent bed.

[0014] While the reagent modules of the '954 and '777 patents operatewell in storing and dissolving reagent beds efficiently, there remainsroom for improvement.

SUMMARY OF THE INVENTION

[0015] An in-line drug delivery pack that connects in-line with anintravenous (IV) line and allows for the mixing of diluent with a drugreagent to be delivered to the patient. An internal drug bed bypassmechanism is tailored to apportion diluent flow between the bypass andthe drug bed. The apportionment is selected to achieve a solutionconcentration suitable for IV administration as the dried reagent isdissolved.

[0016] Thus, both dissolution and precisely tailored dilution areperformed in the same simple device.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 is an elevational view of an IV line drug delivery system,with a joint connecting a diluent line and a concentrated solution drip.

[0018]FIG. 2 is an elevational view of an in-line IV drug deliverysystem, constructed in accordance with a preferred embodiment of thepresent invention.

[0019]FIG. 3 is an elevational cross-section of a drug delivery pack foruse inline along an IV line.

[0020]FIG. 4 is a sectional view taken along lines 4-4 in FIG. 3.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0021] Description of Components

[0022] One drug delivery system is shown in FIG. 1. The intravenous bag1 is connected to a drug delivery bag 5 by means of a Y-connector 20.The Y-connector 20 combines the solutions into an injection line 25 thatis subsequently introduced to the hand 30 or any other body part. Thedrug delivery bag 5 holds pre-formed concentrated solution, which isdiluted for IV injection by fluid from the diluent bag 1. As noted inthe Background section, this arrangement has certain disadvantages.

[0023] With reference to FIG. 2, a drug delivery pack 35 is shownin-line with an intravenous solution bag 1. The solution bag 1 is partof the intravenous delivery system 36. The IV line 3 leads from theintravenous delivery system 36 to the drug delivery pack 35 via Luerlocks 4, and then to an injection site 30, which in this example is at ahuman hand. Those skilled in the art will realize that other injectionsites include but are not limited to the arm, neck and leg.

[0024] Now referring to FIG. 3, a housing 37 of the drug delivery pack35 is preferably composed of a clear material, such as plastic polymeror glass. An inlet 40 in the housing top 45 provides a connectionbetween an input line (not shown), such as an IV line, and the body ofthe housing 37. The inlet 40 includes a collar 42 terminating at one endwith a connection fitting 55 to connect to the diluent source. Thehousing 37 also contains an air vent (not shown) and a terminal outlet160 at the axial terminus of the housing 37 opposite to the inlet 40.The air vent is preferably sealed against fluid flow by an airpermeable/fluid impermeable barrier or a mechanical valve.

[0025] Immediately adjacent to the inlet 40 is a distribution chamber60, defined between an inlet frit 80 and the housing top 45, which areseparated by radial fins 65 protruding from the housing top 45.Referring to FIG. 4, the radial fins 65 are shown in a cross-section,stopping short of a central opening.

[0026] Referring again to FIG. 3, the inlet frit 80 is a porousmaterial, which can be hydrophilic but is preferably hydrophobic. Theporosity of the frit 80 can range from about 5 to about 100 microns,with the preferred range in porosity between about 5 and about 50microns, and more preferably between about 10 and about 20 microns.Exemplary materials are porous polymers and cellulose filters.

[0027] An open bore 90 is located below the inlet frit 80, which is justbelow the distribution chamber 60. Also below the inlet frit 80 is anupstream compression component 85. The illustrated compression component85 takes the form of a cylinder surrounding the open central bore 90.The compression component 85 is composed of open celled polymericmaterial, which upon compression exerts a pressure as a result of memoryof the material. This pressure is measured as a compression deflection(CD) or an indentation load deflection (ILD). In other arrangements, thecompression component can comprise a polymer or metal spring. The bore90 is filled with a core 105 of porous material. The core 105 can betailored as needed, but preferably has a greater porosity in pores perinch (PPI) than the compression component 85.

[0028] Below the compression component 85 is an upper reagent restraint95. In the illustrated embodiment, the upper reagent restraint 95 is adisk of material with a central hole 100 accommodating the core 105. Theupper reagent restraint 95 can be porous or nonporous polymeric orcellulosic material. The upper reagent restraint is preferablyhydrophilic.

[0029] Below the upper reagent restraint 95 is a reagent bed 110. Itconsists of a fluid soluble material suitable for administering to apatient via dissolution and IV drip. The core 105 also extends throughthe reagent bed.

[0030] Below the reagent bed 110 is a lower reagent restraint 115. Thelower reagent restraint 115 comprises a pliable or rigid disk. Therestraint can be similar to the upper restraint 95, and is illustratedwith a lower reagent central hole 120. If pliable, the lower reagentrestraint 115 is preferably backed by a rigid disk 125, as shown. Thelower reagent restraint 115 is preferably hydrophobic.

[0031] The bore 90 thus extends through the compression component 85,the upper reagent restraint 95, the reagent bed 110, the lower reagentrestraint 115 and (if present) the rigid backing 125.

[0032] Below the lower reagent restraint 115 and the rigid backing 125,is a collection area 135. The collection area 135 is defined by thehousing body 37, the lower reagent restraint 115 or the rigid backing125.

[0033] Below the collection area 135 is a terminal frit 140. Theterminal frit 140 consists of porous polymeric material that may haveeither a hydrophobic or hydrophilic nature. Preferably, the terminalfrit 140 is hydrophobic, such that it generates sufficient back-pressureto accumulate fluid in the overlying collection area 135 before passingthe fluid.

[0034] A collection chamber 145 is located below the terminal frit 140.The collection chamber 145 is defined by the terminal frit 140, thebottom of the housing 150, and the bottom radial fins 175 locatedadjacent to the housing outlet 160. The outlet end of the pack 35 isthus similar to the inlet end.

[0035] The housing outlet 160 forms a tube connecting the housingcollection chamber 145 to the exterior of the housing 37. The exteriorterminus of the outlet 160 includes a fitting to enable a sterile,closed connection to the downstream portion of the diluent flow. Boththe inlet 40 and outlet 160 can be covered by port covers (not shown),if desired, to maintain sterility prior to use.

[0036] In operation, with reference to FIG. 2, the drug delivery pack 35is attached in-line to an intravenous administration set 36 including anupstream reservoir 1 of intravenous fluid connected to a tube 3 linkingthe reservoir to the patient. Attachment of the drug delivery pack 35 isaccomplished by in-line Luer connectors 4 at the inlet and outlet of thedrug delivery pack 35. More specifically, on a preexisting IV line, flowis stopped by closing clips (not shown). The intra-line connections areopened and the drug delivery pack 35 is inserted and locked with Luerlocks. Next, the closing clips on the fluid line are opened and diluentflow is reestablished. It will be readily apparent to those skilled inthe art that a variety of other techniques may be used to connect thedrug delivery pack 35 in-line along an IV line. Such techniques includebut are not limited to having an IV bag spike at the inlet of the drugdelivery pack 35 and/or an IV spike receptacle at the outlet associatedwith a drip chamber.

[0037] Referring now to FIG. 3, diluent from the upstream reservoir 1(FIG. 2) enters the housing 37 via the inlet 40 and first encounters theinlet radial fins 65. The inlet radial fins 65 cooperate withback-pressure from the inlet frit 80 promote a uniform distribution ofdiluent across the entire cross-section of the drug delivery pack 35.The downstream fins 65 similarly cooperate with the outlet frit 140 toform a downstream manifold distribution chambers for the solution. Thehydrophobic nature of the inlet frit 80 forces the diluent to theperiphery within the distribution chamber 60 prior to penetration of thefrit 80. Thus, an initially uniform pattern of diluent flow through theupstream portions of the drug delivery pack 35 is established. It willbe readily apparent to one skilled in the art that other arrangementscan also achieve uniform distribution. Furthermore, the drug pack 35would also entail advantages without an initial uniform distribution.

[0038] The uniform face of diluent enters and passes through the uppercompression component 85. After passing through the upper compressioncomponent 85, the diluent encounters the preferred upper reagentrestraint 95 upstream from the reagent bed 110. The hydrophilic natureof the preferred upper reagent restraint 95 thoroughly “wets” therestraint uniformly by capillary action. This serves to provide awetting of the entire reagent bed 110. This is particularly advantageousfor dissolution of hydrophobic reagents.

[0039] A portion of the diluent bypasses the reagent bed 110 bytraveling down the porous central core 105 within the bore 90. Thisdiluent accumulates in the collection area 135 above the hydrophobicterminal frit 140. The diameter of the bore 90 holding the core 105,together with the relative porosity and hydrophobocity of thecompression component 85, restraint 95, reagent bed 110, and restraint115, determines the portion of diluent entering the reagent bed 110, ascompared to that bypassing the bed 110. Partitioning the amount ofdiluent that enters the reagent bed 110 effectively regulates the rateof dissolution of that reagent.

[0040] Desirably, the hydrophobic nature of the preferred lower reagentrestraint 115 retains diluent with the reagent bed 110, enhancing thewetting of the reagent bed 110. Also, a rigid material may be furnishedto provide support for the reagent restraint 115. Such material mayinclude but is not limited to sintered plastics.

[0041] The solution prepared from the dissolving reagent passes throughthe reagent bed 110 and exits into the central core 105 and/or throughthe lower restraint 115.

[0042] In the upper collection area 135, the portion of the diluentwhich bypassed the reagent bed 110 is mixed with the solution formedfrom diluent passing through the reagent bed 110. The solution is thusdiluted within the area 135. Dissolved reagents have time to diffuse toeven out concentration in the preferred embodiment. This is due to thefact that enough solution must gather in the collection area 135 tocreate, preserve and overcome the hydrophobicity of the preferredterminal frit 140. When sufficient solution enters the collection area155 to create sufficient head pressure to overcome the hydrophobicity ofthe terminal frit 140, solution terminal frit 140 and into the lowercollection chamber 145 and into the housing outlet 160. An additionalhydrophobic barrier of varied porosity may also be placed before theoutlet. The collection area 135 can also be created by the use of aspring, rather than the rigid and welded elements 115 or 125, as will beapparent to those skilled in the art.

[0043] As will be apparent to the skilled artisan in view of thediscussion above, the various elements in the drug pack 35 can bearranged to vary the relative diluent flow through the core component105, as compared to diluent flow through the reagent bed 110. Varyingthe relative flows thus varies the concentration of drug solutionexiting the pack 35. For example, for a given set of materials, thediameter of the bore 90 and core element 105 therein can be varied asdesired. Alternatively, for a given bore 90 size, the relative porosityof the core element 105 as compared to that of the upper reagentrestraint 95 can be changed. Varying materials to accomplish differentlevels of hydrophobicity can also influence the relative flow rates. Fora given application, accordingly, the skilled artisan can determine anappropriate set of materials and relative dimensions to achieve adesirable solution concentration. Thus, no separate diluent line needsto be employed, and the overall IV administration system is muchsimplified.

[0044] The skilled artisan will readily appreciate, in view of thedisclosure herein, numerous other manners of varying the relative flowof diluents through the reagent bed as compared to a bypassing flow. Forexample, in contrast to the illustrated central core 90 and core element105 housed therein, a peripheral gap between the reagent bed 110 and thehousing 337 can be created by surrounding the bed with a frit having asmaller diameter than the housing 37, spaced therefrom by periodicspacers or ribs, for example. In yet another arrangement, the centralcore 105 need not extend through each of the elements 85, 95, 110, 115and 125. Note that the inlet frit can also be made hydrophilic to biasfluid flow coming through the inlet 40, through the central core 105,rather than encouraging a uniform flow distribution at the inlet end.Such an arrangement would produce a more dilute solution than use of ahydrophobic inlet frit 80.

[0045] Preferred Materials

[0046] In the preferred embodiment, the inlet frit 80 is polypropylene.The compression component 85 is made of an open cell foam. The centralcore 105 is also made of an open cell foam. The terminal frit 140 iscellulose. The lower reagent restraint 115 is hydrophobic and made ofporous polypropylene, to retain diluent within the reagent bed.

[0047] The collection area 135 is maintained by a polymer spring withgreater force deflection than the upper compression component 85, thusspacing the upper components above the terminal frit 140.

[0048] The terminal frit 140 is hydrophobic to form the collection area135 within the housing 37 upstream of the housing outlet.

[0049] Exemplary Application

[0050] An example of a device for delivery of a typical antibiotic (forexample a cephalosporin like Cefazolin™) with a drug bed 110 of 1000 mgutilizes a housing 37 0.75 inches in internal diameter and a height of1.25 inches. The internal volume of this housing 37 is roughly 9milliliters. For appropriate delivery this drug is administered over aperiod of 40 minutes, forming a total of 60 milliliters of solution atconcentration between 10 and 40 milligrams/milliliter.

[0051] The interior of the housing 37 is divided into two chambers. Theupper chamber contains the compression component 85, the core and thereagent. For exemplary 1000 mg dose of drug, the dry volume is 3.0milliliters. The preferred compression component has a height of 0.875inches. The central cavity 90 within this component 85 has an interiordiameter of 0.25 inches to accommodate the core 105.

[0052] The preferred component 85 has a preferred porosity of about 60to 90 pores per inch (PPI), more preferably 75 PPI, and a preferredcompression load deflection (CLD) of about 0.4 to 0.6 PSI at 25%compression, more preferably 0.5 PSI at this compression. At 65%compression the CLD is preferably about 0.5 to 0.8 PSI, more preferably0.65 PSI. These CLD were determined by measurement of deflection 50square inches of material. It is compressed within the housing to fillthe area upstream of the reagent bed.

[0053] The exemplary core 105 has a height of 0.675 inches and an outerdiameter of 0.225 inches. The prosity of this material is preferably 90to 110 PPI, more preferably 100.

[0054] The reagent bed restraints 95, 115 have a preferred range in poresize of 5 to 25 microns, more preferably about 10 microns. The supportfor the reagent bed restraints 95, 115 preferably has pores of 20 to 80microns, more preferably 40 to 60 microns. The diameter of the hole inthe reagent restraints and the support is about 0.215 inches toaccommodate the core 105.

[0055] The lower chamber 135 is open with a frit 140 at the distal endof the housing 37, adjacent to the outlet 160. The frit 140 between theopen chamber 135 and the outlet 160 preferably has pores of between 5and 25 microns, more preferably about 10 microns. The frit 140 ispreferably hydrophobic, comprising polypropylene. It has a preferredthickness of between 0.25 and 0.75 inches, more preferably 0.5 inches.

[0056] Other variations will be apparent for those skilled in the art.For instance, an increased diameter of the housing 37 could be employedwith an increased core 105 diameter for hydrophilic reagents to decreasethe efficiency of dissolution of the reagent.

What is claimed is:
 1. A drug delivery apparatus comprising: a housing having an inlet port, an outlet port, and at least one terminal frit; a drug reagent bed within the housing, the drug reagent bed in communication with a first fluid flow path between the inlet port and the outlet, wherein the drug reagent bed comprises reagents for the preparation of a solution suitable for intravenous administration; and a second fluid flow path within the housing between the inlet port and the outlet port, wherein the second fluid flow path bypasses the drug reagent bed.
 2. The apparatus of claim 1, further comprising at least one compression component positioned to expert pressure on the drug reagent bed.
 3. The apparatus of claim 2, wherein the at least one terminal frit is hydrophobic.
 4. The apparatus of claim 2, wherein the at least one terminal frit has a porosity from about 5 to 100 microns.
 5. The apparatus of claim 2, wherein the at least one terminal frit has a porosity from about 10 to 20 microns.
 6. The apparatus of claim 1, wherein the second fluid flow path is in the middle of the housing.
 7. The apparatus of claim 1, wherein a plurality of elements housed within the housing are selected to tailor relative flow rates along the first and second paths to control a concentration of solution formed from diluent and the drug reagent bed.
 8. A drug delivery apparatus comprising: a housing having an inlet port and an outlet port, wherein a plurality of elements housed within the housing are selected to tailor relative flow rates along the first and second paths to control a concentration of solution formed from diluent and the drug reagent bed; a drug reagent bed within the housing, the drug reagent bed in communication with a first fluid flow path between the inlet port and the outlet; a second fluid flow path within the housing between the inlet port and the outlet port, the second fluid flow path bypassing the drug reagent bed.
 9. The apparatus of claim 8, further comprising at least one compression component positioned within the housing to exert pressure on the drug reagent bed.
 10. The apparatus of claim 8, further comprising at least one hydrophobic terminal frit.
 11. The apparatus of claim 8, wherein the second fluid flow path is in the middle of the housing.
 12. The apparatus of claim 8, wherein the second fluid flow path is at the periphery of the housing.
 13. The apparatus of claim 8, wherein the drug reagent bed comprises reagents for the preparation of a solution suitable for intravenous administration.
 14. A drug delivery apparatus comprising: a housing having an inlet port, an outlet port, and at least one terminal frit, and at least one compression component; a drug reagent bed within the housing, the drug reagent bed in communication with a first fluid flow path between the inlet port and the outlet, wherein the drug reagent bed comprises reagents for the preparation of a solution suitable for intravenous administration, and the compression component is positioned within the housing to exert pressure on the reagent bed; and a second fluid flow path within the housing between the inlet port and the outlet port, wherein the second fluid flow path bypasses the drug reagent bed.
 15. The apparatus of claim 14, wherein the at least one terminal frit is an inlet frit.
 16. The apparatus of claim 14, wherein the at least one terminal frit is an outlet frit.
 17. The apparatus of claim 14, wherein the at least one terminal frit is hydrophobic.
 18. The apparatus of claim 15, wherein the at least one compression component is positioned upstream of the reagent bed.
 19. The apparatus of claim 18, wherein the compression component comprises a celled polymeric material.
 20. The apparatus of claim 14, wherein a plurality of elements housed within the housing are selected to tailor relative flow rates along the first and second paths to control a concentration of solution formed from diluent and the drug reagent bed. 